Ethylene oxide dosimetry in the mouse.
Ethylene oxide (EO) is a direct-acting mutagen and animal carcinogen used as an industrial intermediate and sterilant with a high potential for human exposure. Understanding the exposure-dose relationship for EO in rodents is critical for developing human EO exposure-dose models. The study reported here examined the dosimetry of EO in male B6C3F1 mice by direct determination of blood EO concentrations. Steady-state blood EO concentrations were measured during a single 4-h nose-only inhalation exposure (0, 50, 100, 200, 300, or 400 ppm EO). In addition, glutathione (GSH) concentrations were measured in liver, lung, kidney, and testis to assess the role of the GSH depletion in the saturable metabolism previously observed in mice (Brown et al., Toxicol. Appl. Pharmacol. 136, 8-19, 1996). Blood EO concentrations were found to increase linearly with exposure concentration up to 200 ppm. Markedly sublinear blood dosimetry was observed at exposure concentrations exceeding 200 ppm. An EO exposure concentration-dependent reduction in tissue GSH levels was observed, with both liver and lung GSH levels significantly depressed at EO exposure concentrations of 100 ppm or greater. Our results also indicate that depletion of GSH is likely responsible for nonlinear dosimetry of EO in mice and that GSH depletion corresponds with reports of dose-rate effects in mice exposed to EO.
Brown
C D
CD
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Asgharian
B
B
Turner
M J
MJ
Fennell
T R
TR
D000280:Administration, Inhalation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005027:Ethylene Oxide / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D012129:Respiratory Function Tests; D013737:Testis / Q000378:metabolism
D005978:Glutathione; D005027:Ethylene Oxide